The applicant for this Mentored Career Development Award (K23) is an M.D. scientist who has performed a productive research fellowship in the mentor?s laboratory. The resources at the Albert Einstein College of Medicine (AECM) include a recently renewed GCRC, a Diabetes Research Center, Core Laboratories with expertise in state-of-the-art technologies pertinent to this application, as well as a K30-funded Clinical Research Training Program that will form the backbone of the training environment. Severe hypoglycemia is the major limitation of intensive treatment of Type 1 diabetes mellitus (T1DM), though such therapy can effectively prevent the microvascular complications of diabetes. It is now well-established that the liver plays a central role in the physiologic response to hypoglycemia by rapidly increasing glucose production (GP), and that this response is dependent in turn on the secretion of the primary counterregulatory hormones glucagon and epinephrine. Dr. Shamoon's laboratory was the first to demonstrate that patients with T1DM have defective GP due to absent glucagon and impaired epinephrine responses to experimental hypoglycemia. Recently, Dr. Shamoon has also identified a non-hormonal component of GP, activated at mild hypoglycemia (approximately 70mg/dl), that is also defective in T1DM. This latter component of the GP response is likely to be due to glucose per se, previously thought to be only activated at much deeper levels of hypoglycemia (< 40 mg/dl). Hepatic glucose fluxes that are involved in GP must include both glycogenolysis and gluconeogenesis, though there is a paucity of data regarding the precise quantitative contributions of each. The central role of the GP in T1DM is emphasized by studies suggesting that glycogenolysis after overnight fasting is defective, and only partially restored by short-term normalization of glycemia. The applicant hypothesizes that the early GP response to hypoglycemia is predominantly dependent on glycogenolysis, and is similarly defective in T1DM. Furthermore, defective glycogenolysis may account for the impaired GP responses due to glucose per se and to the reduced adrenergic drive of secreted epinephrine. The introduction of in vivo nuclear magnetic resonance (NMR) spectroscopy to the study of liver glycogen metabolism provides a powerful new approach. The specific aims are: 1) to study the time course of glycogenolysis and gluconeogenesis in a model of fixed hypoglycemia in non-diabetic and intensively-treated T1DM subjects; and 2) to examine the specific relationship between the GP components due to glucose per se or to glucagon and epinephrine in stepped hypoglycemic clamps in non-diabetic and intensively-treated T1DM subjects. These experiments will involve the combined use of sophisticated metabolic physiology and state-of-the-art 4 Tesla NMR spectroscopy to understand the mechanisms of defective glucose counterregulation.